11-112086915-T-C

Variant names:

• chr11-112086915-T-C
• NM_003002.4:c.8T>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003002.4(SDHD):​c.8T>C​(p.Val3Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDHD NM_003002.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.740

Genes affected

SDHD (HGNC:10683): (succinate dehydrogenase complex subunit D) This gene encodes a member of complex II of the respiratory chain, which is responsible for the oxidation of succinate. The encoded protein is one of two integral membrane proteins anchoring the complex to the matrix side of the mitochondrial inner membrane. Mutations in this gene are associated with the formation of tumors, including hereditary paraganglioma. Transmission of disease occurs almost exclusively through the paternal allele, suggesting that this locus may be maternally imprinted. There are pseudogenes for this gene on chromosomes 1, 2, 3, 7, and 18. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2013]

ENSG00000255292 (HGNC:):

TIMM8B (HGNC:11818): (translocase of inner mitochondrial membrane 8 homolog B) This gene encodes a member of a well-conserved family of proteins with similarity to yeast Tim mitochondrial import proteins. This gene is encoded by a nuclear gene and is transported into the intermembrane space of the mitochondrion. When formed into complexes, these proteins guide membrane-spanning proteins across the mitochondrial intermembrane space before they are added into the mitochondrial inner membrane. This gene is adjacent to succinate dehydrogenase, subunit D (SDHD), in which mutations have been found in affected members of families with hereditary paraganglioma.[provided by RefSeq, Aug 2009]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.056636423).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHD	NM_003002.4	c.8T>C	p.Val3Ala	missense_variant	Exon 1 of 4	ENST00000375549.8	NP_002993.1
TIMM8B	NM_012459.4	c.-192A>G		upstream_gene_variant		ENST00000504148.3	NP_036591.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHD	ENST00000375549.8	c.8T>C	p.Val3Ala	missense_variant	Exon 1 of 4	1	NM_003002.4	ENSP00000364699.3
ENSG00000255292	ENST00000532699.1	n.8T>C		non_coding_transcript_exon_variant	Exon 1 of 6	3		ENSP00000456434.1
TIMM8B	ENST00000504148.3	c.-192A>G		upstream_gene_variant		1	NM_012459.4	ENSP00000422122.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Feb 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V3A variant (also known as c.8T>C), located in coding exon 1 of the SDHD gene, results from a T to C substitution at nucleotide position 8. The valine at codon 3 is replaced by alanine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	0.59
DANN	Benign	0.47
DEOGEN2	Benign	0.15	T;.;.;.;.;.;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.53	T;T;T;T;T;.;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.057	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.068	T
MutationAssessor	Benign	0.46	N;N;.;N;.;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.96	N;.;N;N;N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.53	T;.;T;T;T;T;T
Sift4G	Benign	0.74	T;T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;.;.;.
Vest4		0.063
MutPred		0.29		Gain of disorder (P = 0.0285);Gain of disorder (P = 0.0285);Gain of disorder (P = 0.0285);Gain of disorder (P = 0.0285);Gain of disorder (P = 0.0285);Gain of disorder (P = 0.0285);Gain of disorder (P = 0.0285);
MVP		0.81
MPC		0.23
ClinPred		0.12	T
GERP RS		-7.8
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.019
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-111957639;